The traditional explanation is that the Mississippi flows through a failed rift that extends north from the "successful" Gulf of Mexico rift. The New Madrid earthquake happened at the northern tip of the failed rift. It's the major, but not the only rift/fault system in the area. The area isn't especially active, geologically speaking, but liquefaction makes any earthquake there especially devastating. That's why San Francisco's Marina District (developed on fill) was heavily damaged by the World Series earthquake back in the late 80s. It was actually a fairly minor earthquake by CA standards, but development in areas susceptible to liquefaction made it pretty destructive. Other than for stopping the World Series, the earthquake was most famous for a doubled-decker highway bridge that failed, crushing people under the fallen upper deck. The bridge supports were in marshland. The moral of the story is to ride out earthquakes on solid rock, not wet sediments.
